National Cancer Institute

at the National Institutes of Health

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)

Health Professional Version

Treatment Option Overview

Many of the improvements in childhood cancer survival have been made using
combinations of known and/or new agents that have attempted to improve the
best available, accepted therapy. Clinical trials in pediatrics are designed
to compare potentially better therapy with therapy that is currently accepted
as standard. This comparison may be done in a randomized study of two treatment
arms or by evaluating a single new treatment and comparing the results with
those previously obtained with standard therapy.

All children with non-Hodgkin lymphoma (NHL) should be considered for entry
into a clinical trial. Treatment planning by a multidisciplinary team of
cancer specialists with experience treating tumors of childhood is strongly
recommended to determine, coordinate, and implement treatment to achieve
optimal survival. Children with NHL should be referred for treatment by a
multidisciplinary team of pediatric oncologists at an institution with
experience in treating pediatric cancers. Information about ongoing clinical
trials is available from the NCI Web site.

NHL in children is generally considered to be widely disseminated from the
outset, even when apparently localized; as a result, combination chemotherapy
is recommended for most patients.[1]

In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Early studies demonstrated that the routine use of radiation had no benefit for low-stage (I or II) NHL.[2] It has been demonstrated that prophylactic central nervous system (CNS) radiation can be omitted in lymphoblastic lymphoma.[3,4] It has also been demonstrated that CNS radiation can be eliminated for patients with anaplastic large cell lymphoma and B-cell NHL, even for patients who present with CNS disease.[5,6] Further data to support the limited use of radiation in pediatric NHL comes from the Childhood Cancer Survivor Study.[7] This analysis demonstrated that radiation was a significant risk factor for secondary malignancy and death in long-term survivors.

Treatment of NHL in childhood and adolescence has historically been based on clinical behavior and response to treatment. A study by the Children’s Cancer Group demonstrated that the outcome for lymphoblastic NHL was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma) had superior outcome with short, intensive, pulsed therapy.[8]

Medical Emergencies

There are two potentially life-threatening
clinical situations that are often seen in children with NHL: (1) mediastinal masses and (2) tumor lysis syndrome, most often seen in lymphoblastic and Burkitt or Burkitt-like NHL. These emergent situations should be anticipated in
children with NHL and addressed immediately.

Mediastinal masses

Patients with large mediastinal masses are at risk of cardiac or respiratory
arrest during general anesthesia or heavy sedation.[9] Due to the risks of
general anesthesia or heavy sedation, a careful physiologic and radiographic
evaluation of the patient should be carried out and the least invasive
procedure should be used to establish the diagnosis of lymphoma.[10,11] Bone
marrow aspirate and biopsy should always be performed early in the workup of
these patients. If a pleural effusion is present, a cytologic diagnosis is
frequently possible using thoracentesis. In those children who present with
peripheral adenopathy, a lymph node biopsy under local anesthesia and in an
upright position may be possible.[12] In situations in which the above
diagnostic procedures are not fruitful, consideration of a computed tomography (CT)–guided core
needle biopsy should be contemplated. This procedure can frequently be carried
out using light sedation and local anesthesia before proceeding to more
invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans, can be done with the patient on their side or prone. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy
are the procedures of choice when other diagnostic modalities fail to establish
the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the
diagnosis or treatment of childhood lymphoma. Occasionally, it will not be
possible to perform a diagnostic operative procedure because of the risk of
general anesthesia or heavy sedation. In these situations, preoperative
treatment with steroids or localized radiation therapy should be considered.
Since preoperative treatment may affect the ability to obtain an accurate
tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of
general anesthesia or heavy sedation is thought to be alleviated.

Tumor lysis syndrome

Tumor lysis syndrome results from rapid breakdown of malignant cells, resulting
in a number of metabolic abnormalities, most notably hyperuricemia,
hyperkalemia, and hyperphosphatemia. Hyperhydration and allopurinol or
rasburicase (urate oxidase) are essential components of therapy in all patients except those with the most limited disease.[13-17] An initial prephase consisting of low-dose
cyclophosphamide and vincristine does not obviate the need for
allopurinol or rasburicase and hydration. Gastrointestinal bleeding, obstruction, and
(rarely) perforation may occur. Hyperuricemia and tumor lysis syndrome,
particularly when associated with ureteral obstruction, frequently result in
life-threatening complications. Patients with NHL should be managed only in
institutions having pediatric tertiary care facilities.

Role of Radiographic Imaging in Childhood NHL

Radiographic imaging is essential in the staging of patients with NHL. Ultrasound may be the preferred method for assessment of an abdominal mass, but CT scan and, more recently, magnetic resonance imaging (MRI) have been used for staging. Radionucleotide bone scans should be considered for patients where bone involvement is suspected.

The role of functional imaging in pediatric NHL is controversial. Gallium scans have been replaced by fluorodeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers.[18] A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.[19,20] While the International Harmonization Project for PET (now called the International Working Group) response criteria have been attempted in adults, they have yet to be evaluated in pediatric populations.[18,21] This International Working Group has updated their response criteria for malignant lymphoma to include PET, immunohistochemistry, and flow cytometry data.[20]

The value of PET scanning for staging pediatric NHL is under investigation.[22] Data support that PET identifies more abnormalities than CT scanning, but it is unclear whether this should be used to change therapy.[23]

The use of PET to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, and this is also under investigation in pediatric NHL. However, there are no data in pediatric NHL to support the hypothesis that early response to therapy assessed by PET has prognostic value.

Caution should be used in making the diagnosis of relapsed disease based solely on imaging because false-positive results are common.[24-28] There are also data demonstrating that PET scanning can produce false-negative results.[29] Before undertaking changes in therapy based on residual masses noted by imaging, a biopsy to prove residual disease is warranted.